Lyme disease, a tick-transmitted, immune-mediated, spirochetal infection in children and adults, usually begins in summer with a characteristic skin lesion, erythema chronicum migrans, that may be followed weeks to months later by meningo-encephalitis, cranial or peripheral neuritis, myocarditis, or by migratory, intermittent or chronic arthritis. We plan to define the natural history, prognosis, treatment, epidemiology, etiology and pathogenesis of this illness. To accomplish these objectives, a network of physicians has been established to refer patients with the disease. The natural history of the disorder will be described from the serial examination of these patients. Antibiotic therapy regimens will be studied for each stage of the illness. Blood, cerebrospinal fluid, joint fluid, skin and synovial biopsy specimens from patients will be cultured for the I. dammini spirochete. Specific serologic tests will be developed for diagnosis, and the frequency of symptomatic and asymptomatic infection will be determined during consecutive summers in a stable, island population. Spirochetal antigen and antibody will be sought in immune complexes in serum and joint fluid, the effects of the causative agent and a serum factor upon lymphocyte function will be studied, and the inter-actions among the causative agent, immunogenetic determinants, circulating immune complexes and lymphocytes will be examined. To understand further the pathogenesis, an animal model for Lyme disease will be sought. This work will provide important information about the diagnosis and treatment of Lyme disease, and the studies of pathogenesis may have implications for other rheumatic diseases. In particular, the question of a persistent infectious agent being necessary for continued disease activity, as opposed to triggering by such an agent followed by autoimmunity, is of central importance in a number of rheumatic diseases.